Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis

作者：Quirke Anne Marie; Lugli Elena Birgitta; Wegner Natalia; Hamilton Bart C; Charles Peter; Chowdhury Muslima; Ytterberg A Jimmy; Zubarev Roman A; Potempa Jan; Culshaw Shauna; Guo Yonghua; Fisher Benjamin A; Thiele Geoffrey; Mikuls Ted R; Venables Patrick J W^*

来源：Annals of the Rheumatic Diseases, 2014, 73(1): 263-269.

DOI：10.1136/annrheumdis-2012-202726

• Rheumatoid Arthritis
• Ant-CCP
• Autoimmunity

Background Rheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking Porphyromonas gingivalis to RA. P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response. %26lt;br%26gt;Objectives To examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues. %26lt;br%26gt;Methods PPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another P gingivalis protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82). %26lt;br%26gt;Results Recombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122U/ml) compared with controls (median 70U/ml; p%26lt;0.05) and PD (median 60U/ml; p%26lt;0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA. %26lt;br%26gt;Conclusions The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy.

• 出版日期2014-1